U.S. patent application number 15/038027 was filed with the patent office on 2016-10-13 for anti-cancer agents and preparation thereof.
The applicant listed for this patent is PURDUE RESEARCH FOUNDATON. Invention is credited to Arun K. Ghosh.
Application Number | 20160297831 15/038027 |
Document ID | / |
Family ID | 53180106 |
Filed Date | 2016-10-13 |
United States Patent
Application |
20160297831 |
Kind Code |
A1 |
Ghosh; Arun K. |
October 13, 2016 |
ANTI-CANCER AGENTS AND PREPARATION THEREOF
Abstract
Embodiments of the present invention provide, among other
compounds, a family of spliceosome-inhibiting compounds that can be
used as therapeutic anti-cancer agents. The compounds are
synthesized in a process that includes the catalytic cross
metathesis of a cyclic epoxy alcohol to an amide.
Inventors: |
Ghosh; Arun K.; (West
Lafayette, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PURDUE RESEARCH FOUNDATON |
West Lafayette |
IN |
US |
|
|
Family ID: |
53180106 |
Appl. No.: |
15/038027 |
Filed: |
November 19, 2014 |
PCT Filed: |
November 19, 2014 |
PCT NO: |
PCT/US14/66458 |
371 Date: |
May 19, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61906133 |
Nov 19, 2013 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/18 20180101; A61P
13/08 20180101; C07D 493/10 20130101; A61K 31/5377 20130101; A61K
31/535 20130101; A61P 11/00 20180101; A61K 47/6803 20170801; C07D
309/14 20130101; A61P 15/00 20180101; C07D 407/12 20130101; A61P
43/00 20180101; A61K 31/336 20130101; A61K 31/495 20130101; A61K
45/06 20130101; A61P 13/12 20180101; A61K 31/35 20130101; A61P
35/00 20180101 |
International
Class: |
C07D 493/10 20060101
C07D493/10; A61K 31/5377 20060101 A61K031/5377; A61K 45/06 20060101
A61K045/06; A61K 31/35 20060101 A61K031/35; C07D 309/14 20060101
C07D309/14; A61K 47/48 20060101 A61K047/48 |
Goverment Interests
STATEMENT OF U.S. GOVERNMENT SUPPORT
[0002] This invention was made with government support under
GM053386 awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1-32. (canceled)
33. A compound according to Formula I or a pharmaceutically
acceptable salt thereof: ##STR00065## wherein R.sup.1 and R.sup.2
are independently selected from the group consisting of H, OH,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.2-6-alkenyloxy,
--(CH.sub.2).sub.nC(O)NR.sup.16R.sup.17, wherein R.sup.16 and
R.sup.17 are selected independently from the group consisting of H,
C.sub.1-6-alkyl, and C.sub.1-6-alkyl substituted with one to three
groups independently selected from halo, hydroxy, C.sub.1-6-alkoxy,
and aryl; or R.sup.16 and R.sup.17, together with the nitrogen atom
to which they are bound, form a 5- to 6-membered heterocyclic or
heteroaromatic ring, and C.sub.1-6-alkyl substituted with one to
three groups independently selected from halo, hydroxy,
C.sub.1-6-alkoxy, and O-hydroxy protecting group; R.sup.3 and
R.sup.4 are selected independently from the group consisting of OH,
C.sub.1-6-alkyl (optionally substituted with Cl, F, NO.sub.2, OH,
or LG, wherein LG is a leaving group such as a --O-- mesyl,
--O-tosyl or --O-besyl leaving group), C(O)R.sup.13, F, Cl,
NO.sub.2, wherein each R.sup.13 is independently H or
C.sub.1-6-alkyl; or R.sup.3 and R.sup.4, together with the carbon
atom to which they are bound, form an epoxide ring; R.sup.5 is
selected from the group consisting of H, a hydroxyl protecting
group, C.sub.1-6-alkyl, C(O)R.sup.13, C(O)OR.sup.13, and
C(O)NR.sup.14R.sup.15; R.sup.6 is selected from the group
consisting of H and C.sub.1-6-alkyl; and R.sup.7 is
C.sub.1-6-alkyl; and R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are
independently selected from the group consisting of H and
C.sub.1-6-alkyl R.sup.12 is C(O)NR.sup.14R.sup.15; each R.sup.13 is
independently H or C.sub.1-6-alkyl, and R.sup.14 and R.sup.15
together with the nitrogen atom to which they are bound, form a 5-
to 6-membered heterocyclic or heteroaromatic ring.
34. The compound according to claim 33 or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting C.sub.1-6-alkyl
and C.sub.1-6-alkoxy; R.sup.3 and R.sup.4, together with the carbon
atom to which they are bound, form an epoxide ring; R.sup.5 is
selected from the group consisting of H, a hydroxyl protecting
group, and C.sub.1-6-alkyl.
35. The compound according to claim 34 or a pharmaceutically
acceptable salt thereof, wherein R.sup.5 is H; and R.sup.8 is
C.sub.1-6-alkyl.
36. The compound according to claim 35 or a pharmaceutically
acceptable salt thereof, wherein the compound conforms to the
formula: ##STR00066## wherein X is selected from the group
consisting of O, NH, NMe, and CO.sub.2Et; and R is selected from
the group consisting of Me, Et, i-Pr, phenyl, and benzyl.
37. The compound according to claim 35 or a pharmaceutically
acceptable salt thereof, wherein X is NH.
38. The compound according to claim 35 or a pharmaceutically
acceptable salt thereof, wherein the compound is: ##STR00067##
39. A compound according to Formula IX: ##STR00068## wherein
R.sup.6 is selected from the group consisting of H and
C.sub.1-6-alkyl; and R.sup.7 is C.sub.1-6-alkyl; and R.sup.8 is
selected from the group consisting of H and C.sub.1-6-alkyl.
40. The compound according to claim 39, wherein the compound is of
the formula: ##STR00069##
41. A compound according to Formula X: ##STR00070## wherein R.sup.6
is selected from the group consisting of H and C.sub.1-6-alkyl; and
R.sup.7 is C.sub.1-6-alkyl; and R.sup.8 and R.sup.9 are
independently selected from the group consisting of H and
C.sub.1-6-alkyl.
42. The compound according to claim 39, wherein the compound is of
the formula ##STR00071##
43. An antibody conjugate, comprising at least one compound
according to claim 33 conjugated to an antibody.
44. A process for preparing a compound according to Formula IX:
##STR00072## the process comprising contacting a compound according
to Formula VIII: ##STR00073## with an olefin in the presence of an
olefin metathesis catalyst whereby olefin metathesis is effected,
wherein R.sup.6 is selected from the group consisting of H and
C.sub.1-6-alkyl; and R.sup.7 is C.sub.1-6-alkyl; and R.sup.8 is
selected from the group consisting of and C.sub.1-6-alkyl.
45. The process according to claim 44, wherein the catalyst is:
##STR00074##
46. The process according claim 44, wherein the compound according
to Formula IX is: ##STR00075## the compound according to Formula
VIII is: ##STR00076## the olefin is the compound: ##STR00077##
Wherein Ts is toluene-sulfonyl, and wherein the product resulting
from the olefin metathesis is contacted with t-BuOK, whereby
compound according to Formula IX is prepared.
47. A pharmaceutical composition comprising a therapeutically
effective amount of a compound or a pharmaceutically acceptable
salt thereof according to claim 33 and one or more pharmaceutically
acceptable carriers, diluents, excipients or combinations
thereof.
48. A method for treating a patient suffering from cancer,
comprising administering to the patient a therapeutically effective
amount of a compound or a pharmaceutically acceptable salt thereof
according to claim 33.
49. A compound or a pharmaceutically acceptable salt thereof
according to claim 33 for treating a patient in need of relief from
cancer.
50. A compound or a pharmaceutically acceptable salt thereof
according to claim 33 for use in the preparation of a medicament
for treating a patient in need of relief from cancer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
Provisional Appl. Ser. No. 61/906,133, filed Nov. 19, 2013, which
is incorporated by reference as if fully set forth herein.
FIELD OF THE INVENTION
[0003] Embodiments of the present invention relate to compounds
that can be used to treat disease, e.g., cancer, and compositions
and prodrugs including, or resulting in, these compounds. Methods
of making the compounds are also disclosed.
BACKGROUND
[0004] The American Cancer Society estimates that cancer costs the
U.S. economy almost $200 billion per year due to the costs of
medical treatment (about $80 billion per year) and lost
productivity due to death and/or disability (about $120 billion per
year). Of course, there is also a human toll as loved ones are
diagnosed, treated, and sometimes die from many forms of cancer.
Because of the high social and economic costs of cancer, new cancer
treatments are a top priority for institutions such as the U.S.
National Institutes of Health as well as major pharmaceutical
companies.
SUMMARY
[0005] Proliferative diseases, such as cancer, cause harm to the
body with the rapid growth of cells that interfere with the health
function of nearby (or far-away) tissues. Because the cells
replicate quickly, compounds that disrupt transcription pathways
are valuable in fighting the disease. That is, if it is possible to
disrupt the function of one or more proteins that play a role in a
transcription pathway, the proliferation (and potential metastasis)
of cancerous cells will be limited. Such a disruption would at
least help a patient gain additional months or years of life.
[0006] One family of protein complexes involved in transcription
pathways are spliceosomes. Spliceosomes typically include over 100
proteins that work together to control the excision of exons (i.e.,
splicing of introns) from genomic material during the
transcription. Compounds that interfere with the function of
spliceosomes or a spliceosome-regulation protein are valuable for
slowing or stopping the spread of proliferative disease.
[0007] Embodiments of the present invention include compounds that
are effective at limiting the growth of proliferative cells and
useful as therapeutic cancer agents. Embodiments of the present
invention also include compositions comprising these compounds as
well as pro-drugs that result in the compounds when administered to
a patient. The compounds are useful for the treatment of cancer, in
particular solid tumor cell cancers, such as breast, lung,
cervical, prostate, ovarian, pancreatic, and renal cell cancer. The
compounds, compositions, and prodrugs can be administered to a
patient in need of treatment for proliferative disease, e.g.,
cancer.
[0008] Embodiments of the present invention additionally include
methods of making the therapeutic compounds of the various
embodiments of the invention. The methods include the cross
metathesis of an epoxy alcohol fragment with an amide fragment in
the presence of a catalyst. In an embodiment, the method includes
forming the epoxy alcohol fragment from an (R)-isopropylidene
glyceraldyhyde, forming the amide fragment using a
Corey-Bakshi-Shibata (CBS) reduction, an Achmatowicz rearrangement,
a stereoselective Michael addition, and coupling the first and
second fragments with a cross-metathesis reaction. The method can
be performed in about 20 steps under standard reaction conditions
and proceeds with high enantiomeric efficiency (>98% ee) and a
good yield.
DETAILED DESCRIPTION
[0009] Embodiments of the invention include a family of novel
compounds that can be used as therapeutic anti-cancer agents. The
agents can be synthesized in a straightforward synthesis that
includes a catalytic cross metathesis of a cyclic epoxy alcohol to
a amide, as described herein.
[0010] Various embodiments of the present invention are directed to
compounds having Formula I and stereoisomers, pharmaceutically
acceptable salts, prodrugs (e.g., ester) or antibody conjugates
(see, e.g., U.S. Pat. No. 8,663,643, which is incorporated by
reference as if fully set forth herein) thereof:
##STR00001##
wherein R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, OH, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.2-6-alkenyloxy, --(CH.sub.2).sub.nC(O)NR.sup.16R.sup.17
(wherein R.sup.16 and R.sup.17 are selected independently from the
group consisting of H, C.sub.1-6-alkyl, and C.sub.1-6-alkyl
substituted with one to three groups independently selected from
halo, hydroxy, C.sub.1-6-alkoxy, and aryl; or R.sup.16 and
R.sup.17, together with the nitrogen atom to which they are bound,
form a 5- to 6-membered heterocyclic or heteroaromatic ring), and
C.sub.1-6-alkyl substituted with one to three groups independently
selected from halo, hydroxy, C.sub.1-6-alkoxy, and O-hydroxy
protecting group; R.sup.3 and R.sup.4 are selected independently
from the group consisting of OH, C.sub.1-6-alkyl (optionally
substituted with Cl, F, NO.sub.2, OH, or LG, wherein LG is a
leaving group such as a --O-mesyl, --O-tosyl or --O-besyl leaving
group), C(O)R.sup.13, F, Cl, NO.sub.2, wherein each R.sup.13 is
independently H or C.sub.1-6-alkyl; or R.sup.3 and R.sup.4,
together with the carbon atom to which they are bound, form an
epoxide ring; R.sup.5 and R.sup.12 are independently selected from
the group consisting of H, a hydroxyl protecting group,
C.sub.1-6-alkyl, C(O)R.sup.13, C(O)OR.sup.13, and
C(O)NR.sup.14R.sup.15, wherein each R.sup.13 is independently H or
C.sub.1-6-alkyl, and wherein R.sup.14 and R.sup.15 are selected
independently from the group consisting of H and C.sub.1-6-alkyl;
or R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are bound, form a 5- to 6-membered heterocyclic or hetero
aromatic ring; R.sup.6 is selected from the group consisting of H
and C.sub.1-6-alkyl; and R.sup.7 is C.sub.1-6-alkyl; and R.sup.8,
R.sup.9, R.sup.10, and R.sup.11 are independently selected from the
group consisting of H and C.sub.1-6-alkyl.
[0011] Various other embodiments of the present invention are
directed to compounds having Formula Ia and stereoisomers,
pharmaceutically acceptable salts, prodrugs (e.g., ester) or
antibody conjugates thereof:
##STR00002##
wherein R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, OH, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.2-6-alkenyloxy, --(CH.sub.2).sub.nC(O)NR.sup.16R.sup.17
(wherein R.sup.16 and R.sup.17 are selected independently from the
group consisting of H, C.sub.1-6-alkyl, and C.sub.1-6-alkyl
substituted with one to three groups independently selected from
halo, hydroxy, C.sub.1-6-alkoxy, and aryl; or R.sup.16 and
R.sup.17, together with the nitrogen atom to which they are bound,
form a 5- to 6-membered heterocyclic or heteroaromatic ring), and
C.sub.1-6-alkyl substituted with one to three groups independently
selected from halo, hydroxy, C.sub.1-6-alkoxy, and O-hydroxy
protecting group; R.sup.3 and R.sup.4 are selected independently
from the group consisting of OH, C.sub.1-6-alkyl (optionally
substituted with Cl, F, NO.sub.2, OH, or LG, wherein LG is a
leaving group such as a --O-mesyl, --O-tosyl or --O-besyl leaving
group), C(O)R.sup.13, F, Cl, NO.sub.2, wherein each R.sup.13 is
independently H or C.sub.1-6-alkyl; or R.sup.3 and R.sup.4,
together with the carbon atom to which they are bound, form an
epoxide ring; R.sup.5 and R.sup.12 are independently selected from
the group consisting of H, a hydroxyl protecting group,
C.sub.1-6-alkyl, C(O)R.sup.13, C(O)OR.sup.13, and
C(O)NR.sup.14R.sup.15, wherein each R.sup.13 is independently H or
C.sub.1-6-alkyl, and wherein R.sup.14 and R.sup.15 are selected
independently from the group consisting of H and C.sub.1-6-alkyl;
or R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are bound, form a 5- to 6-membered heterocyclic or hetero
aromatic ring; R.sup.6 is selected from the group consisting of H
and C.sub.1-6-alkyl; and R.sup.7 is C.sub.1-6-alkyl; and R.sup.8,
R.sup.9, R.sup.10, and R.sup.11 are independently selected from the
group consisting of H and C.sub.1-6-alkyl.
[0012] Still other embodiments of the present invention are
directed to a process for preparing a compound having Formula I and
a stereoisomer, pharmaceutically acceptable salt, prodrug (e.g.,
ester) or antibody conjugate thereof:
##STR00003##
wherein R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, OH, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.2-6-alkenyloxy, --(CH.sub.2).sub.nC(O)NR.sup.16R.sup.17
(wherein R.sup.16 and R.sup.17 are selected independently from the
group consisting of H, C.sub.1-6-alkyl, and C.sub.1-6-alkyl
substituted with one to three groups independently selected from
halo, hydroxy, C.sub.1-6-alkoxy, and aryl; or R.sup.14 and
R.sup.15, together with the nitrogen atom to which they are bound,
form a 5- to 6-membered heterocyclic or heteroaromatic ring), and
C.sub.1-6-alkyl substituted with one to three groups independently
selected from halo, hydroxy, C.sub.1-6-alkoxy, and O-hydroxy
protecting group; R.sup.3 and R.sup.4 are selected independently
from the group consisting of OH, C.sub.1-6-alkyl (optionally
substituted with Cl, F, NO.sub.2, OH, or LG, wherein LG is a
leaving group such as a --O-mesyl, --O-tosyl or --O-besyl leaving
group), C(O)R.sup.13, F, Cl, NO.sub.2, wherein each R.sup.13 is
independently H or C.sub.1-6-alkyl; or R.sup.3 and R.sup.4,
together with the carbon atom to which they are bound, form an
epoxide ring; R.sup.5 and R.sup.12 are independently selected from
the group consisting of H, a hydroxyl protecting group,
C.sub.1-6-alkyl, C(O)R.sup.13, C(O)OR.sup.13, and
C(O)NR.sup.14R.sup.15, wherein each R.sup.13 is independently H or
C.sub.1-6-alkyl, and wherein R.sup.14 and R.sup.15 are selected
independently from the group consisting of H and C.sub.1-6-alkyl;
or R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are bound, form a 5- to 6-membered heterocyclic or hetero
aromatic ring; R.sup.6 is selected from the group consisting of H
and C.sub.1-6-alkyl; and R.sup.7 is C.sub.1-6-alkyl; R.sup.8,
R.sup.9, R.sup.10 and R.sup.11 are independently selected from the
group consisting of H and C.sub.1-6-alkyl; the method comprising
converting a compound of the Formula II:
##STR00004##
to a compound of the Formula III:
##STR00005##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are each
defined herein; and contacting a compound of Formula III with a
compound of the Formula IV:
##STR00006##
wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, and
R.sup.12 are defined herein; in the presence of an olefin
metathesis catalyst to form a compound of Formula I.
[0013] As used herein, the term "C.sub.1-6-alkyl" refers to
monovalent saturated aliphatic hydrocarbyl groups having from 1 to
6 carbon atoms. This term includes, but is not limited to, linear
and branched hydrocarbyl groups such as methyl (CH.sub.3--), ethyl
(CH.sub.3CH.sub.2--), n-propyl (CH.sub.3CH.sub.2CH.sub.2--),
isopropyl ((CH.sub.3).sub.2CH, n-butyl
(CH.sub.3CH.sub.2CH.sub.2CH.sub.2--), isobutyl
((CH.sub.3).sub.2CHCH.sub.2--), sec-butyl
((CH.sub.3)(CH.sub.3CH.sub.2)CH--), t-butyl ((CH.sub.3).sub.3C,
n-pentyl (CH.sub.3CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and
neopentyl ((CH.sub.3).sub.3CCH.sub.2--). The term C.sub.1-6-alkyl
also includes cycloalkyl groups including, but not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0014] As used herein, the term "C.sub.2-6-alkenyl" (e.g., in
C.sub.2-6-alkenyloxy) in refers to monovalent unsaturated
hydrocarbyl groups having from 2 to 6 carbon atoms. This term
includes, but is not limited to, linear and branched hydrocarbyl
groups such as vinyl (CH.sub.2.dbd.CH--), propenyl
(CH.sub.2.dbd.CH.sub.2CH.sub.2--), and isopropenyl
((CH.sub.3)(CH.sub.2)C--). The term C.sub.2-6-alkyl also includes
cycloalkenyl groups including, but not limited to, cyclopentenyl
and cyclohexenyl.
[0015] The term "heteroaryl" as used herein refers to an aromatic
heterocycle ring of 5 to 14 members, such as 5 to 6 members, having
at least one heteroatom selected from nitrogen, oxygen and sulfur,
and containing at least 1 carbon atom. Heteroaryls may be
monocyclic, bicyclic, or tricyclic ring systems. Representative
heteroaryls are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl,
benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl,
indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,
thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl,
phthalazinyl, quinazolinyl, pyrimidyl, azepinyl, oxepinyl, and
quinoxalinyl
[0016] As used herein, the term "aryl" broadly refers to cyclic
aromatic hydrocarbons that do not contain heteroatoms in the ring.
Such aryl groups may be substituted or unsubstituted. Aryl groups
include, but are not limited to, phenyl, biphenyl, fluorenyl,
phenanthrenyl, and naphthyl groups.
[0017] As used herein, the term "heterocycle" or "heterocycloalkyl"
as used herein refers to 5- to 14-membered ring systems, such as 5-
to 6-membered ring systems, which are either saturated,
unsaturated, and which contain from 1 to 4 heteroatoms
independently selected from nitrogen, oxygen and sulfur, and
wherein the nitrogen and sulfur heteroatoms may be optionally
oxidized, and the nitrogen heteroatom may be optionally
quaternized. Heterocycles may be monocyclic, bicyclic, or tricyclic
ring systems. The bicyclic or tricyclic ring systems may be
spiro-fused. The bicyclic and tricyclic ring systems may encompass
a heterocycle or heteroaryl fused to a benzene ring. The
heterocycle may be attached via any heteroatom or carbon atom.
Heterocycles include heteroaryls as defined above. Representative
examples of heterocycles include, but are not limited to,
aziridinyl, oxiranyl, thuiranyl, triazolyl, tetrazolyl, azirinyl,
diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl,
oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl,
pyrrolyl, oxazinyl, thiazinyl, diazinyl, dioxanyl, triazinyl,
tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl,
furanyl, furazanyl, pyridinyl, oxazolyl, benzoxazolyl,
benzisoxazolyl, thiazolyl, benzthiazolyl, thiophenyl, pyrazolyl,
triazolyl, pyrimidinyl, benzimidazolyl, isoindolyl, indazolyl,
benzodiazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl,
purinyl, indolyl, isoquinolinyl, quinolinyl, and quinazolinyl.
[0018] The term "hydroxy" refers to the group --OH.
[0019] The term "hydroxy protecting group" refers to protecting
groups for an --OH group. Suitable hydroxy protecting groups as
well as suitable conditions for protecting and deprotecting
particular functional groups are well known in the art. For
example, numerous such protecting groups are described in T. W.
Greene and P. G. M. Wuts, PROTECTING GROUPS IN ORGANIC SYNTHESIS,
3rd ed., Wiley, New York. Such hydroxy protecting groups include
C.sub.1-6 alkyl ethers, benzyl ethers, p-methoxybenzyl ethers,
silyl ethers, and the like.
[0020] The term "C.sub.1-6-alkoxy" refers to the group
--O--(C.sub.1-6-alkyl) wherein C.sub.1-6-alkyl is defined herein.
C.sub.1-6-alkoxy includes, but is no limited to, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and
n-pentoxy.
[0021] In some embodiments, a compound of the Formula III is a
compound of the formula:
##STR00007##
wherein R.sup.1, R.sup.2, and R.sup.5 are defined herein.
[0022] In some embodiments, a compound of the Formula IV is a
compound of the formula:
##STR00008##
wherein R.sup.6-R.sup.12 are defined herein.
[0023] In some embodiments, the compound of Formula IV, or a
stereoisomer, pharmaceutically acceptable salt, prodrug (e.g.,
ester) or antibody conjugate thereof, is prepared from a compound
of the Formula V:
##STR00009##
wherein R.sup.8 is defined herein. The compound of the Formula IV
can be prepared via process comprising: contacting a compound of
the Formula V with a suitable reducing agent (e.g., a
Corey-Bakshi-Shibata (CBS) reduction using borane and a chiral
oxazaborolidine) to obtain a compound of the Formula VI:
##STR00010##
wherein R.sup.8 is defined herein; contacting the compound of the
Formula VI with a suitable metal catalyst (e.g., VO(acac).sub.2 to
effect an Achmatowicz rearrangement) to obtain a compound of the
Formula VII:
##STR00011##
wherein R.sup.8 is defined herein; contacting the compound of the
Formula VII with a compound of the R.sup.7Li, wherein R.sup.7 is
defined herein, with a suitable metal salt (e.g.,
CuBr.S(CH.sub.3).sub.2) to obtain a compound of the Formula
VIII:
##STR00012##
contacting the compound of the Formula VIII with a suitable olefin
metathesis catalyst (e.g., a suitable Grubbs' second generation
olefin metathesis catalyst), wherein R.sup.7 and R.sup.8 are
defined herein, to obtain a compound of the Formula IX:
##STR00013##
wherein R.sup.6, R.sup.7, and R.sup.8 are defined herein;
converting the compound of the Formula IX to a compound of the
Formula X:
##STR00014##
wherein R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are defined herein,
under reductive amination conditions; and contacting the compound
of the Formula X with a compound of the Formula XI:
##STR00015##
to obtain a compound of the Formula IV.
[0024] In some embodiments, the compound of the Formula VI is a
compound of the formula:
##STR00016##
[0025] In some embodiments, the compound of the Formula VII is a
compound of the formula:
##STR00017##
[0026] In some embodiments, the compound of the Formula VIII is a
compound of the formula:
##STR00018##
[0027] In some embodiments, the compound of the Formula IX is a
compound of the formula:
##STR00019##
[0028] In some embodiments, the compound of the Formula X is a
compound of the formula:
##STR00020##
[0029] In some embodiments, the compound of the Formula XI is a
compound of the formula:
##STR00021##
[0030] In some embodiments, the compound of the Formula I is a
compound of the formula:
##STR00022##
or a pharmaceutically acceptable salt, prodrug (e.g., ester) or
antibody conjugate thereof.
[0031] In other embodiments, the compound of the Formula I is a
compound of the formula:
##STR00023##
or a pharmaceutically acceptable salt, prodrug (e.g., ester) or
antibody conjugate thereof.
[0032] Embodiments of the invention include any one of compounds
Z1-Z7, as well as combinations thereof, which are potent spliceo
some inhibitors, and may be administered as anti-cancer agents and
which can be synthesized by the methods described herein:
##STR00024##
and pharmaceutically acceptable salts, prodrugs (e.g., ester) or
antibody conjugates thereof. The compounds may be included in a
composition or delivered as a prodrug. The compounds Z1-Z7 can be
prepared via the processes described herein for compounds of the
Formula I.
[0033] "Pharmaceutically acceptable salt" generally refers to
pharmaceutically acceptable salts of a compound, which salts are
derived from a variety of organic and inorganic counter ions well
known in the art and include, by way of example only, sodium,
potassium, calcium, magnesium, ammonium, and tetraalkylammonium;
and when the molecule contains a basic functionality, salts of
organic or inorganic acids, such as hydrochloride, hydrobromide,
tartrate, mesylate, acetate, maleate, and oxalate.
[0034] As used herein, the term "prodrug" means a derivative of a
compound that can hydrolyze, oxidize, or otherwise react under
biological conditions (in vitro or in vivo) to provide an active
compound, particularly a compound of the embodiments of the present
invention. Examples of prodrugs include, but are not limited to,
derivatives and metabolites of a compound of the invention that
include biohydrolyzable moieties such as biohydrolyzable amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate
analogues. Specific prodrugs of compounds with carboxyl functional
groups are the lower alkyl esters of the carboxylic acid. The
carboxylate esters are conveniently formed by esterifying any of
the carboxylic acid moieties present on the molecule. Prodrugs can
typically be prepared using well-known methods, such as those
described by Burger's Medicinal Chemistry and Drug Discovery 6th
ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application
of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers
GmbH).
[0035] Those of ordinary skill in the art will recognize that
compounds described herein (e.g., compounds Z1-Z7) contain chiral
centers. All diastereomers of the compounds described herein are
contemplated herein, as well as racemates. Those of ordinary skill
in the art will also recognize that compounds described herein
(e.g., compounds Z1-Z7) comprise at three two double bonds each of
which can have the E (engegen) or the Z (zusammen) configuration.
All isomers of the compounds described herein (e.g., E,E,E; Z,Z,Z;
E,Z,E; E,E,Z; Z,E,E; Z,E,Z, and Z,Z,E) are contemplated herein.
[0036] Various embodiments of the present invention also
contemplate pharmaceutical compositions comprising one or more
compounds of the various embodiments of the present invention (e.g.
compounds Z1-Z7) and one or more pharmaceutically acceptable
carriers, diluents, excipients or combinations thereof. A
"pharmaceutical composition" refers to a chemical or biological
composition suitable for administration to a subject (e.g.,
mammal). Such compositions may be specifically formulated for
administration via one or more of a number of routes, including but
not limited to buccal, cutaneous, epicutaneous, epidural, infusion,
inhalation, intraarterial, intracardial, intracerebroventricular,
intradermal, intramuscular, intranasal, intraocular,
intraperitoneal, intraspinal, intrathecal, intravenous, oral,
parenteral, pulmonary, rectally via an enema or suppository,
subcutaneous, subdermal, sublingual, transdermal, and transmucosal.
In addition, administration can by means of capsule, drops, foams,
gel, gum, injection, liquid, patch, pill, porous pouch, powder,
tablet, or other suitable means of administration.
[0037] A "pharmaceutical excipient" or a "pharmaceutically
acceptable excipient" comprises a carrier, sometimes a liquid, in
which an active therapeutic agent is formulated. The excipient
generally does not provide any pharmacological activity to the
formulation, though it may provide chemical and/or biological
stability, and release characteristics. Examples of suitable
formulations can be found, for example, in Remington, The Science
And Practice of Pharmacy, 20th Edition, (Gennaro, A. R., Chief
Editor), Philadelphia College of Pharmacy and Science, 2000, which
is incorporated by reference in its entirety.
[0038] As used herein "pharmaceutically acceptable carrier" or
"excipient" includes any and all solvents, dispersion media,
coatings, antibacterial and antifungal agents, isotonic and
absorption delaying agents that are physiologically compatible. In
one embodiment, the carrier is suitable for parenteral
administration. Alternatively, the carrier can be suitable for
intravenous, intraperitoneal, intramuscular, sublingual, or oral
administration. Pharmaceutically acceptable carriers include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersion. The use of such media and agents for pharmaceutically
active substances is well known in the art. Except insofar as any
conventional media or agent is incompatible with the active
compound, use thereof in the pharmaceutical compositions of the
invention is contemplated. Supplementary active compounds can also
be incorporated into the compositions.
[0039] Pharmaceutical compositions may be sterile and stable under
the conditions of manufacture and storage. The composition can be
formulated as a solution, microemulsion, liposome, or other ordered
structure suitable to high drug concentration. The carrier can be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (e.g., glycerol, propylene glycol, and liquid
polyethylene glycol), and suitable mixtures thereof. The proper
fluidity can be maintained, for example, by the use of a coating
such as lecithin, by the maintenance of the required particle size
in the case of dispersion and by the use of surfactants.
[0040] In many cases, it will be preferable to include isotonic
agents, for example, sugars, polyalcohols such as mannitol,
sorbitol, or sodium chloride in the composition. Prolonged
absorption of the injectable compositions can be brought about by
including in the composition an agent which delays absorption, for
example, monostearate salts and gelatin. Moreover, the compounds
described herein can be formulated in a time release formulation,
for example in a composition that includes a slow release polymer.
The active compounds can be prepared with carriers that will
protect the compound against rapid release, such as a controlled
release formulation, including implants and microencapsulated
delivery systems. Biodegradable, biocompatible polymers may be
used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic
acid, collagen, polyorthoesters, polylactic acid and polylactic,
polyglycolic copolymers (PLG). Many methods for the preparation of
such formulations are known to those skilled in the art.
[0041] Oral forms of administration are also contemplated herein.
The pharmaceutical compositions of the present invention may be
orally administered as a capsule (hard or soft), tablet (film
coated, enteric coated or uncoated), powder or granules (coated or
uncoated) or liquid (solution or suspension). The formulations may
be conveniently prepared by any of the methods well-known in the
art. The pharmaceutical compositions of the present invention may
include one or more suitable production aids or excipients
including fillers, binders, disintegrants, lubricants, diluents,
flow agents, buffering agents, moistening agents, preservatives,
colorants, sweeteners, flavors, and pharmaceutically compatible
carriers.
[0042] For each of the recited embodiments, the compounds can be
administered by a variety of dosage forms as known in the art. Any
biologically-acceptable dosage form known to persons of ordinary
skill in the art, and combinations thereof, are contemplated.
Examples of such dosage forms include, without limitation, chewable
tablets, quick dissolve tablets, effervescent tablets,
reconstitutable powders, elixirs, liquids, solutions, suspensions,
emulsions, tablets, multi-layer tablets, bi-layer tablets,
capsules, soft gelatin capsules, hard gelatin capsules, caplets,
lozenges, chewable lozenges, beads, powders, gum, granules,
particles, microparticle s, dispersible granules, cachets, douches,
suppositories, creams, topicals, inhalants, aerosol inhalants,
patches, particle inhalants, implants, depot implants, ingestibles,
injectables (including subcutaneous, intramuscular, intravenous,
and intradermal), infusions, and combinations thereof.
[0043] Other compounds which can be included by admixture are, for
example, medically inert ingredients (e.g., solid and liquid
diluent), such as lactose, dextrosesaccharose, cellulose, starch or
calcium phosphate for tablets or capsules, olive oil or ethyl
oleate for soft capsules and water or vegetable oil for suspensions
or emulsions; lubricating agents such as silica, talc, stearic
acid, magnesium or calcium stearate and/or polyethylene glycols;
gelling agents such as colloidal clays; thickening agents such as
gum tragacanth or sodium alginate, binding agents such as starches,
arabic gums, gelatin, methylcellulose, carboxymethylcellulose or
polyvinylpyrrolidone; disintegrating agents such as starch, alginic
acid, alginates or sodium starch glycolate; effervescing mixtures;
dyestuff; sweeteners; wetting agents such as lecithin, polysorbates
or laurylsulphates; and other therapeutically acceptable accessory
ingredients, such as humectants, preservatives, buffers and
antioxidants, which are known additives for such formulations.
[0044] Liquid dispersions for oral administration can be syrups,
emulsions, solutions, or suspensions. The syrups can contain as a
carrier, for example, saccharose or saccharose with glycerol and/or
mannitol and/or sorbitol. The suspensions and the emulsions can
contain a carrier, for example a natural gum, agar, sodium
alginate, pectin, methylcellulose, carboxymethylcellulose, or
polyvinyl alcohol.
[0045] The amount of active compound in a therapeutic composition
according to various embodiments of the present invention may vary
according to factors such as the disease state, age, gender,
weight, patient history, risk factors, predisposition to disease,
administration route, pre-existing treatment regime (e.g., possible
interactions with other medications), and weight of the individual.
Dosage regimens may be adjusted to provide the optimum therapeutic
response. For example, a single bolus may be administered, several
divided doses may be administered over time, or the dose may be
proportionally reduced or increased as indicated by the exigencies
of therapeutic situation.
[0046] "Dosage unit form," as used herein, refers to physically
discrete units suited as unitary dosages for the mammalian subjects
to be treated; each unit containing a predetermined quantity of
active compound calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the invention are
dictated by and directly dependent on the unique characteristics of
the active compound and the particular therapeutic effect to be
achieved, and the limitations inherent in the art of compounding
such an active compound for the treatment of sensitivity in
individuals. In therapeutic use for treatment of conditions in
mammals (e.g., humans) for which the compounds of the present
invention or an appropriate pharmaceutical composition thereof are
effective, the compounds of the present invention may be
administered in an effective amount. The dosages as suitable for
this invention may be a composition, a pharmaceutical composition
or any other compositions described herein.
[0047] For each of the recited embodiments, the dosage is typically
administered once, twice, or thrice a day, although more frequent
dosing intervals are possible. The dosage may be administered every
day, every 2 days, every 3 days, every 4 days, every 5 days, every
6 days, and/or every 7 days (once a week). In one embodiment, the
dosage may be administered daily for up to and including 30 days,
preferably between 7-10 days. In another embodiment, the dosage may
be administered twice a day for 10 days. If the patient requires
treatment for a chronic disease or condition, the dosage may be
administered for as long as signs and/or symptoms persist. The
patient may require "maintenance treatment" where the patient is
receiving dosages every day for months, years, or the remainder of
their lives. In addition, the composition of this invention may be
to effect prophylaxis of recurring symptoms. For example, the
dosage may be administered once or twice a day to prevent the onset
of symptoms in patients at risk, especially for asymptomatic
patients.
[0048] The compositions described herein may be administered in any
of the following routes: buccal, epicutaneous, epidural, infusion,
inhalation, intraarterial, intracardial, intracerebroventricular,
intradermal, intramuscular, intranasal, intraocular,
intraperitoneal, intraspinal, intrathecal, intravenous, oral,
parenteral, pulmonary, rectally via an enema or suppository,
subcutaneous, subdermal, sublingual, transdermal, and transmucosal.
The preferred routes of administration are buccal and oral. The
administration can be local, where the composition is administered
directly, close to, in the locality, near, at, about, or in the
vicinity of, the site(s) of disease or systemic, wherein the
composition is given to the patient and passes through the body
widely, thereby reaching the site(s) of disease. Local
administration can be administration to the cell, tissue, organ,
and/or organ system, which encompasses and/or is affected by the
disease, and/or where the disease signs and/or symptoms are active
or are likely to occur. Administration can be topical with a local
effect, composition is applied directly where its action is
desired. Administration can be enteral wherein the desired effect
is systemic (non-local), composition is given via the digestive
tract. Administration can be parenteral, where the desired effect
is systemic, composition is given by other routes than the
digestive tract.
[0049] In some embodiments, the various embodiments of the present
invention contemplate compositions comprising a therapeutically
effective amount of one or more compounds of the various
embodiments of the present invention (e.g. at least one compound
Z1-Z7). In some embodiments, the compositions are useful in a
method for treating cancer, the method comprising administering a
therapeutically effective amount of one or more compounds of the
various embodiments of the present invention to a patient in need
thereof. In some aspects, the various embodiments of the present
invention contemplate a compound of the various embodiments of the
present invention for use as a medicament for treating a patient in
need of relief from cancer. In some embodiments, the cancer
includes, but is not limited to, solid tumor cell cancers
including, but not limited to, pancreatic cancer; bladder cancer;
colorectal cancer; breast cancer, including metastatic breast
cancer; prostate cancer, including androgen-dependent and
androgen-independent prostate cancer; renal cancer, including,
e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung
cancer, including, e.g., non-small cell lung cancer (NSCLC),
bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung;
ovarian cancer, including, e.g., progressive epithelial or primary
peritoneal cancer; cervical cancer; gastric cancer; esophageal
cancer; head and neck cancer, including, e.g., squamous cell
carcinoma of the head and neck; melanoma; neuroendocrine cancer,
including metastatic neuroendocrine tumors; brain tumors,
including, e.g., glioma, anaplastic oligodendroglioma, adult
glioblastoma multiforme, and adult anaplastic astrocytoma; bone
cancer; and soft tissue sarcoma. Examples of hematologic malignancy
include acute myeloid leukemia (AML); chronic myelogenous leukemia
(CML), including accelerated CML and CML blast phase (CML-BP);
acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia
(CLL); Hodgkins disease (HD); non-Hodgkin's lymphoma (NHL),
including follicular lymphoma and mantle cell lymphoma; B-cell
lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's
macroglobulinemia; myelodysplastic syndromes (MDS), including
refractory anemia (RA), refractory anemia with ringed siderblasts
(RARS), (refractory anemia with excess blasts (RAEB), and RAEB in
transformation (RAEB-T); and myeloproliferative syndromes, such as
breast, lung, cervical, prostate, ovarian, pancreatic, and renal
cell cancer.
[0050] The term "therapeutically effective amount" as used herein,
refers to that amount of one or more compounds of the various
embodiments of the present invention (e.g. at least one compound
Z1-Z7) that elicits a biological or medicinal response in a tissue
system, animal or human, that is being sought by a researcher,
veterinarian, medical doctor or other clinician, which includes
alleviation of the symptoms of the disease or disorder being
treated. In some embodiments, the therapeutically effective amount
is that which may treat or alleviate the disease or symptoms of the
disease at a reasonable benefit/risk ratio applicable to any
medical treatment. However, it is to be understood that the total
daily usage of the compounds and compositions described herein may
be decided by the attending physician within the scope of sound
medical judgment. The specific therapeutically-effective dose level
for any particular patient will depend upon a variety of factors,
including the condition being treated and the severity of the
condition; activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, gender
and diet of the patient: the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidentally with the specific compound employed; and like
factors well known to the researcher, veterinarian, medical doctor
or other clinician. It is also appreciated that the therapeutically
effective amount can be selected with reference to any toxicity, or
other undesirable side effect, that might occur during
administration of one or more of the compounds described
herein.
[0051] In some embodiments, a therapeutically effective amounts of
the compounds of the various embodiments of the present invention
can range from approximately 0.05 to 50 mg per kilogram body weight
of the recipient per day; such as about 0.1-25 mg/kg/day, or from
about 0.5 to 10 mg/kg/day. Thus, for administration to a 70 kg
person, for instance, the dosage range can be about 35-70 mg per
day.
[0052] In some embodiments, one or more of the compounds of the
various embodiments of the present invention can be administered in
combination with at least one other anticancer agent including, but
not limited to docetaxel, paclitaxel, bevacizumab
(Avastin.TM.).
INCORPORATION BY REFERENCE
[0053] References and citations to other documents, such as
patents, patent applications, patent publications, journals, books,
papers, web contents, have been made throughout this disclosure.
All such documents are hereby incorporated herein by reference in
their entirety for all purposes. Such documents include, but are
not limited to: [0054] (1) (a) Nakajima, H.; Sato, B.; Fujita, T.;
Takase, S.; Terano, H.; Okuhara, M. J. Antibiot. 1996, 49,
1196-1203. (b) Nakajima, H.; Hori, Y.; Terano, H.; Okuhara, M.;
Manda, T.; Matsumoto, S.; Shimomura, K. J. Antibiot. 1996, 49,
1204-1211. (c) Nakajima, H.; Takase, S.; [0055] Terano, H.; Tanaka,
H. J. Antibiot. 1997, 50, 96-99. [0056] (2) (a) Motoyoshi, H.;
Horigome, M.; Ishigami, K.; Yoshida, T.; Horinouchi, S.; Yoshida,
M.; Watanabe, H.; Kitahara, T. Biosci. Biotechnol. Biochem. 2004,
68, 2178-2182. (b) Kaida, D.; Motoyoshi, H.; Tashiro, E.; Nojima,
T.; Hagiwara, M.; Ishigami, K.; Watanabe, H.; Kitahara, T.;
Yoshida, T.; Nakajima, H.; Tani, T.; Horinouchi, S.; Yoshida, M.
Nature Chem. Biol. 2007, 3, 576-583. (c) Zhang, F.; He, H.-Y.;
Tang, M.-C.; Tang, Y.-M.; Zhou, Q.; Tang, G.-L. J. Am. Chem. Soc.
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Chem. Soc. 2000, 122, 10482-10483. (b) Thompson, C. F.; Jamison, T.
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EQUIVALENTS
[0080] Various modifications of the invention and many further
embodiments thereof, in addition to those shown and described
herein, will become apparent to those skilled in the art from the
full contents of this document, including references to the
scientific and patent literature cited herein. The subject matter
herein contains important information, exemplification and guidance
that can be adapted to the practice of this invention in its
various embodiments and equivalents thereof.
[0081] The terms and expressions which have been employed are used
as terms of description and not of limitation, and there is no
intention that in the use of such terms and expressions of
excluding any equivalents of the features shown and described or
portions thereof, but it is recognized that various modifications
are possible within the scope of the invention claimed. Thus, it
should be understood that although the present invention has been
specifically disclosed by preferred embodiments and optional
features, modification and variation of the concepts herein
disclosed may be resorted to by those of ordinary skill in the art,
and that such modifications and variations are considered to be
within the scope of this invention as defined by the appended
claims.
EXAMPLES
[0082] The present invention can be better understood by reference
to the following example which is offered by way of illustration.
The present invention is not limited to the example(s) given
herein.
[0083] A synthetic scheme for compounds Z1-Z7 is shown below with
respect to FR901464 (1) and Spliceostatin A (2), shown below, which
are not compounds of the invention.
##STR00025##
[0084] Nonetheless, it should be understood that the synthetic
scheme is generally unique, and greatly simplifies the synthetic
steps as compared to, e.g., the total synthesis of 1 described by
Thompson, C. F., et al., J. Am. Chem. Soc. 122 10482-10483 (2000);
and Thompson, C. F., et al., J. Am. Chem. Soc. 123: 9974-9983
(2001), both of which are incorporated by reference as if fully set
forth herein. Compounds Z1-Z7 can be synthesized by making suitable
substitutions in the synthesis of the cyclic epoxy alcohol
(compound 3 in Scheme 1) as shown in Scheme 1 herein.
Example 1
Synthesis of Epoxy Alcohol Segment 3
##STR00026##
[0086] The synthesis of epoxy alcohol segment 3 is shown in Scheme
1. Commercially available bromo ketone 11 was protected as its
dithiane derivative. Lithiation of the resulting dithiane with
t-BuLi at 78.degree. C. for 1 hours followed by reaction with
(R)-isopropylidene glyceraldehyde provided a mixture (1:1) of
diastereomers 12 and 13 in 61% yield in two steps. This lack of
stereoselectivity was somewhat unexpected, especially given the
presence of chelating atoms at both R and .beta. positions of
(R)-isopropylidene glyceraldehyde. In an attempt to improve
antidiastereoselectivity, we investigated this addition reaction in
the presence of a number of Lewis acids such as CeCl.sub.3,
ZnCl.sub.2, and MgBr.sub.2, in THF and ether. However, there was no
further improvement in the diastereomeric ratio.
[0087] The isomers were separated by silica gel chromatography. The
syn-isomer 12 was converted to desired anti-isomer 13 by a
Mitsunobu reaction in the presence of p-nitrobenzoic acid followed
by NaOH-mediated hydrolysis of the benzoate ester. The hydroxyl
group of 13 was protected as a para-methoxy benzyl (PMB) ether, and
subsequent removal of the isopropylidene group was carried out by
the addition of p-TsOH in a one pot operation to provide diol 14.
The primary alcohol was selectively mono-tosylated using tosyl
chloride (TsCl) and Et.sub.3N in the presence of dibutyltin oxide.
Reaction of the resulting mono-tosylate with an excess of
Corey-Chaykovsky dimethylsulfonium, methylide prepared by treatment
of trimethylsulfonium iodide with n-BuLi, furnished allylic alcohol
15 in 84% yield. A similar functional group transformation was
previously reported by Carreira and co-workers. See Bode, J. W. and
Carreira E. M., J. Org. Chem. 66: 6410-6424 (2001), which is
incorporated by reference as if fully set forth herein. The
dithiane group of 15 was then removed by using an excess of
Hg(ClO.sub.4).sub.2 in methanol in the presence of dry
2,6-lutidine. This condition resulted in the formation of the
corresponding methyl ketal as a mixture of anomers, which upon
treatment with a catalytic amount of p-TsOH in methanol at
0.degree. C. provided a single diastereomer 16. Removal of the PMB
group in 16 with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
followed by alcohol directed epoxidation with m-chloroperbenzoic
acid (m-CPBA) afforded the desired epoxy alcohol segment 3
stereoselectively as a white solid in 19% overall yield from 11 (8
steps). The methyl ketal 3 is quite stable and easy to handle for
subsequent reactions.
##STR00027##
Example 2
Synthesis of Amide 4
##STR00028##
[0089] Amide 4 can be synthesized in a two-step process, shown
below as Scheme 2A and Scheme 2B. The preparation of the Z-allylic
acetate side chain 7 is shown in Scheme 2A. Optically active
alcohol 10 was efficiently prepared by utilizing a catalytic
asymmetric addition protocol reported by Trost and co-workers to
provide 10>98% enantiomeric efficiency (ee). Saponification of
methyl ester 10 with aqueous LiOH followed by acetylation with
acetyl chloride provided acetate 17 in excellent yield.
Hydrogenation over Lindlar's catalyst afforded the desired
cis-alkene 7.
##STR00029##
[0090] The synthesis of amide segment 4 is shown in Scheme 2B,
where the amide segment 4 has the structure:
##STR00030##
[0091] Enantioselective reduction of commercially available acetyl
furan 18 with (S)-2-Me-CBS catalyst (also known as
(S)-5,5-Diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine) and
BH3.Me.sub.2S afforded chiral alcohol 9 in 94% yield (93% ee). An
Achmatowicz rearrangement was then carried out by treatment of
alcohol 9 with t-BuO.sub.2H in the presence of a catalytic amount
of VO(acac).sub.2 to furnish a hemiketal, which was directly
reduced to enone 19 as a single diastereomer by employing the
protocol described by Kishi and co-workers. Our subsequent
synthetic plan required installation of the C20 (S)-methyl-bearing
stereocenter. We elected to carry out a 1,4-addition to enone 19.
Accordingly, treatment of 19 with MeLi/CuBr.Me.sub.2S at
-78.degree. C. for 2 hours provided the desired pyranone 8 in
excellent yield (92%) and diastereoselectivity (25:1 dr, by .sup.1H
and .sup.13C NMR analysis). The observed diastereoselectivity can
be explained based upon the conformational analysis of enone 19.
The stereochemical outcome of Michael addition can be rationalized
by assuming stereoelectronically favorable axial attack of the
cuprate as shown in the transition-state model 20.
[0092] Pyranone 8 and known alkene 21 were then subjected to
cross-metathesis conditions using a Grubbs'-type second generation
catalyst (Scholl, M., et al., Org. Lett. 1: 953-956 (1999),
incorporated by reference as if fully set forth herein):
##STR00031##
to provide the corresponding terminal tosylate. Treatment of the
resulting tosylate with t-BuOK in DMSO at 75.degree. C. for 12
hours resulted in diene 22 via base promoted elimination in 41%
yield over two steps. Reductive amination of 22 with ammonium
acetate and NaBH.sub.3 CN afforded the corresponding primary amine
6 as a major product (6:1 dr, by .sup.1H and .sup.13C NMR
analysis). The crude amine 6 and its epimer were directly treated
with acid 7 using standard amidation conditions to give the amide 4
along with minor C-14 epimer, which were separated by column
chromatography.
##STR00032##
[0093] In the final step, FR901464 (1), Spliceostatin A (2), a
compound of the invention, i.e., compounds Z1-Z7, or similar
compounds can be created with the cross-metathesis of the epoxy
alcohol segment 3 and the amide segment 4, as shown in Scheme 3.
With the stereoselective syntheses of segments epoxy alcohol 3
(Scheme 1) and amide 4 (Scheme 2A/B), we then turned our attention
to construct the C6-C7 double bond of the target molecules. As
shown in Scheme 3, cross-metathesis of the two fragments proceeded
smoothly in the presence of Grubbs' second-generation catalyst to
afford spliceostatin A (2) as a white solid in 57% isolated yield
based upon one recycle of unreacted 3 and 4 under the same
conditions. Compounds Z1-Z7 can be formed with similar yields and
enantiomeric efficiency. The removal of the methylketal in 2 was
achieved by exposure of 2 to pyridinium p-toluene sulfonate (PPTS)
in wet THF at 0.degree. C., which provided FR901464 (1) as a white
powder in good yield. The .sup.1H and .sup.13C NMR of our synthetic
FR901464[[.alpha.].sub.D-13.0 (c 0.45, CH.sub.2Cl.sub.2)] is
identical to the reported spectra of natural [[.alpha.].sub.D-12.0
(c 0.5, CH.sub.2Cl.sub.2)] and synthetic FR901464.
##STR00033##
[0094] Thus, embodiments of the present invention provide a concise
and enantioselective strategy for the syntheses of FR901464,
Spliceostatin A, or compounds Z1-Z7 in about 20 total steps with
the longest linear sequence of about 10 steps. The syntheses
includes the use of readily available chiral pool
(R)-isopropylidene glyceraldyhyde 5 to form an A-ring fragment, a
CBS reduction, an Achmatowicz rearrangement, and a stereoselective
Michael addition for the construction of a B-ring fragment, and a
cross-metathesis reaction for coupling the two fragments. The
synthesis is short, convergent and amenable to the synthesis of
structural variants not disclosed, which are intended to be
encompassed in the synthetic methods.
Example 3
[0095] The compound of the formula:
##STR00034##
was synthesized according to the synthetic scheme shown below in
Scheme 4:
##STR00035## ##STR00036## ##STR00037##
Example 4
[0096] The compound of the formulae:
##STR00038##
were synthesized according to the synthetic scheme shown below in
Scheme 5:
##STR00039##
Example 4
[0097] The compound of the formula:
##STR00040##
was synthesized according to the synthetic scheme shown below in
Scheme 6:
##STR00041##
[0098] The following embodiments are provided, the numbering of
which is not to be construed as designating levels of
importance:
[0099] Embodiment 1 relates to a process for preparing a compound
having Formula I, or a stereoisomer, pharmaceutically acceptable
salt, prodrug (e.g., ester) or antibody conjugate thereof:
##STR00042##
wherein R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, OH, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.2-6-alkenyloxy, --(CH.sub.2).sub.nC(O)NR.sup.16R.sup.17
(wherein R.sup.16 and R.sup.17 are selected independently from the
group consisting of H, C.sub.1-6-alkyl, and C.sub.1-6-alkyl
substituted with one to three groups independently selected from
halo, hydroxy, C.sub.1-6-alkoxy, and aryl; or R.sup.16 and
R.sup.17, together with the nitrogen atom to which they are bound,
form a 5- to 6-membered heterocyclic or heteroaromatic ring), and
C.sub.1-6-alkyl substituted with one to three groups independently
selected from halo, hydroxy, C.sub.1-6-alkoxy, and O-hydroxy
protecting group; R.sup.3 and R.sup.4 are selected independently
from the group consisting of OH, C.sub.1-6-alkyl (optionally
substituted with Cl, F, NO.sub.2, OH, or LG, wherein LG is a
leaving group), C(O)R.sup.13, F, Cl, NO.sub.2, wherein each
R.sup.13 is independently H or C.sub.1-6-alkyl; or R.sup.3 and
R.sup.4, together with the carbon atom to which they are bound,
form an epoxide ring; R.sup.5 and R.sup.12 are independently
selected from the group consisting of H, a hydroxyl protecting
group, C.sub.1-6-alkyl, C(O)R.sup.13, C(O)OR.sup.13, and
C(O)NR.sup.14R.sup.15, wherein each R.sup.13 is independently H or
C.sub.1-6-alkyl, and wherein R.sup.14 and R.sup.15 are selected
independently from the group consisting of H and C.sub.1-6-alkyl;
or R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are bound, form a 5- to 6-membered heterocyclic or hetero
aromatic ring; R.sup.6 is selected from the group consisting of H
and C.sub.1-6-alkyl; and R.sup.7 is C.sub.1-6-alkyl; R.sup.8,
R.sup.9, le, and R.sup.11 are independently selected from the group
consisting of H and C.sub.1-6-alkyl; the method comprising
converting a compound of the Formula II:
##STR00043##
to a compound of the Formula III:
##STR00044##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are defined
herein; and contacting a compound of Formula III with a compound of
the Formula IV:
##STR00045##
wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, and
R.sup.12 are defined herein; in the presence of an olefin
metathesis catalyst to form a compound of Formula I.
[0100] Embodiment 2 relates to the process of Embodiment 1, wherein
the compound of the Formula III is a compound of the formula:
##STR00046##
R.sup.1 and R.sup.2 are independently selected from the group
consisting of H, OH, C.sub.1-6-alkyl, and C.sub.1-6-alkyl
substituted with one to three groups independently selected from
halo, hydroxy, C.sub.1-6-alkoxy, and O-hydroxy protecting group;
R.sup.5 is selected from the group consisting of H, a hydroxyl
protecting group, C.sub.1-6-alkyl, C(O)R.sup.13, C(O)OR.sup.13, and
C(O)NR.sup.14R.sup.15, wherein each R.sup.13 is independently H or
C.sub.1-6-alkyl, and wherein R.sup.14 and R.sup.15 are selected
independently from the group consisting of H and C.sub.1-6-alkyl;
or R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are bound, form a 5- to 6-membered heterocyclic or
heteroaromatic ring.
[0101] Embodiment 3 relates to the process of Embodiments 1-2,
wherein R.sup.1 is H; R.sup.2 is C.sub.1-6-alkyl and R.sup.5 is
H.
[0102] Embodiment 4 relates to the process of Embodiments 1-3,
wherein R.sup.2 is --CH.sub.3.
[0103] Embodiment 5 relates to the process of Embodiments 1-4,
wherein the compound of the Formula IV is a compound of the
formula:
##STR00047##
R.sup.6 is selected from the group consisting of H and
C.sub.1-6-alkyl; and R.sup.7 is C.sub.1-6-alkyl; R.sup.8, R.sup.9,
R.sup.10, and R.sup.11 are independently selected from the group
consisting of H and C.sub.1-6-alkyl; and R.sup.12 is selected from
the group consisting of H, a hydroxyl protecting group,
C.sub.1-6-alkyl, C(O)R.sup.13, C(O)OR.sup.13, and
C(O)NR.sup.14R.sup.15, wherein each R.sup.13 is independently H or
C.sub.1-6-alkyl, and wherein R.sup.14 and R.sup.15 are selected
independently from the group consisting of H and C.sub.1-6-alkyl;
or R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are bound, form a 5- to 6-membered heterocyclic or
heteroaromatic ring.
[0104] Embodiment 6 relates to the process of Embodiments 1-5,
wherein R.sup.6, R.sup.7, R.sup.8, and R.sup.11 are independently
C.sub.1-6-alkyl; R.sup.9 and R.sup.10 are H; and R.sup.12 is
C(O)R.sup.13, wherein R.sup.13 is C.sub.1-6-alkyl.
[0105] Embodiment 7 relates to the process of Embodiments 1-6,
wherein R.sup.6, R.sup.7, R.sup.8, and R.sup.11 are --CH.sub.3;
R.sup.9 and R.sup.10 are H; and R.sup.12 is C(O)R.sup.13, wherein
R.sup.13 is --CH.sub.3.
[0106] Embodiment 8 relates to the process of Embodiments 1-7,
wherein the compound of the Formula I is a compound selected from
the group consisting of:
##STR00048##
and pharmaceutically acceptable salts, prodrugs or antibody
conjugate thereof.
[0107] Embodiment 9 relates to a process for preparing a compound
having Formula IV, or a stereoisomer, pharmaceutically acceptable
salt, prodrug or antibody conjugate thereof:
##STR00049##
wherein R.sup.6 is selected from the group consisting of H and
C.sub.1-6-alkyl; R.sup.7 is C.sub.1-6-alkyl; R.sup.8, R.sup.9,
R.sup.10, and R.sup.11 are independently selected from the group
consisting of H and C.sub.1-6-alkyl; and R.sup.12 is selected from
the group consisting of H, a hydroxyl protecting group,
C.sub.1-6-alkyl, C(O)R.sup.13, C(O)OR.sup.13, and
C(O)NR.sup.14R.sup.15, wherein each R.sup.13 is independently H or
C.sub.1-6-alkyl, and wherein R.sup.14 and R.sup.15 are selected
independently from the group consisting of H and C.sub.1-6-alkyl;
or R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are bound, form a 5- to 6-membered heterocyclic or hetero
aromatic ring; the process comprising: contacting a compound of the
Formula V:
##STR00050##
wherein R.sup.8 is defined herein, with a reducing agent to obtain
a compound of the Formula VI:
##STR00051##
wherein R.sup.8 is defined herein; contacting the compound of the
Formula VI with a metal catalyst to obtain a compound of the
Formula VII:
##STR00052##
wherein R.sup.8 is defined herein; contacting the compound of the
Formula VII with a compound of the R.sup.7Li, wherein R.sup.7 is
defined herein, with a metal salt to obtain a compound of the
Formula VIII:
##STR00053##
contacting the compound of the Formula VIII with an olefin
metathesis catalyst, wherein R.sup.7 and R.sup.8 are defined
herein, to obtain a compound of the Formula IX:
##STR00054##
wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are
defined herein; converting the compound of the Formula IX to a
compound of the Formula X:
##STR00055##
wherein R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are defined herein,
under reductive amination conditions; and contacting the compound
of the Formula X with a compound of the Formula XI:
##STR00056##
wherein R.sup.10, R.sup.11, and R.sup.12 are defined herein; to
obtain a compound of the Formula IV.
[0108] Embodiment 10 relates to the process of Embodiment 9,
wherein the reducing agent is a chiral reducing agent.
[0109] Embodiment 11 relates to the process of Embodiment 10,
wherein the chiral reducing agent comprises a chiral
oxazoborolidine.
[0110] Embodiment 12 relates to the process of Embodiment 9,
wherein the metal catalyst effects an Achmatowicz
rearrangement.
[0111] Embodiment 13 relates to the process of Embodiment 9,
wherein the metal catalyst is VO(acac).sub.2.
[0112] Embodiment 14 relates to the process of Embodiment 9,
wherein the metal salt comprises CuBr.
[0113] Embodiment 15 relates to the process of Embodiments 9-14,
wherein the compound of the Formula VI is a compound of the
formula:
##STR00057##
wherein R.sup.8 is selected from the group consisting of H and
C.sub.1-6-alkyl.
[0114] Embodiment 16 relates to the process of Embodiments 9-15,
wherein R.sup.8 is --CH.sub.3.
[0115] Embodiment 17 relates to the process of Embodiments 9-16,
wherein the compound of the Formula VII is a compound of the
formula:
##STR00058##
wherein R.sup.8 is selected from the group consisting of H and
C.sub.1-6-alkyl.
[0116] Embodiment 18 relates to the process of Embodiments 9-17,
wherein R.sup.8 is --CH.sub.3.
[0117] Embodiment 19 relates to the process of Embodiments 9-18,
wherein, the compound of the Formula VIII is a compound of the
formula:
##STR00059##
wherein R.sup.7 and R.sup.8 are independently C.sub.1-6-alkyl.
[0118] Embodiment 20 relates to the process of Embodiments 9-19,
wherein the compound of the Formula IX is a compound of the
formula:
##STR00060##
wherein R.sup.6 is selected from the group consisting of H and
C.sub.1-6-alkyl; R.sup.7 is C.sub.1-6-alkyl; and R.sup.8 is
selected from the group consisting of H and C.sub.1-6-alkyl.
[0119] Embodiment 21 relates to the process of Embodiments 9-20,
wherein the compound of the Formula X is a compound of the
formula:
##STR00061##
wherein R.sup.6 is selected from the group consisting of H and
C.sub.1-6-alkyl; R.sup.7 is C.sub.1-6-alkyl; and R.sup.8 and
R.sup.9 are independently selected from the group consisting of H
and C.sub.1-6-alkyl.
[0120] Embodiment 22 relates to the process of Embodiments 9-21,
wherein the compound of the Formula XI is a compound of the
formula:
##STR00062##
R.sup.10 and R.sup.11 are independently selected from the group
consisting of H and C.sub.1-6-alkyl; and R.sup.12 is selected from
the group consisting of H, a hydroxyl protecting group,
C.sub.1-6-alkyl, C(O)R.sup.13, C(O)OR.sup.13, and
C(O)NR.sup.14R.sup.15, wherein each R.sup.13 is independently H or
C.sub.1-6-alkyl, and wherein R.sup.14 and R.sup.15 are selected
independently from the group consisting of H and C.sub.1-6-alkyl;
or R.sup.14 and R.sup.15, together with the nitrogen atom to which
they are bound, form a 5- to 6-membered heterocyclic or hetero
aromatic ring.
[0121] Embodiment 23 relates to the process of Embodiments 9-22,
wherein R.sup.11 is C.sub.1-6-alkyl; R.sup.10 is H; and R.sup.12 is
C(O)R.sup.13, wherein R.sup.13 is C.sub.1-6-alkyl.
[0122] Embodiment 24 relates to the process of Embodiments 9-23,
wherein R.sup.11 is --CH.sub.3.
[0123] Embodiment 25 relates to a compound selected from the group
consisting of:
##STR00063##
or a salt, prodrug or antibody conjugate thereof.
[0124] Embodiment 26 relates to a pharmaceutical composition
comprising one or more of the compounds of Embodiment 25, or salts,
prodrugs or antibody conjugates thereof, and a pharmaceutically
acceptable carrier or excipient.
[0125] Embodiment 27 relates to a prodrug that is converted in vivo
into a compound selected from the group consisting of:
##STR00064##
[0126] Embodiment 28 relates to a method of treating cancer in a
subject in need of such treatment, comprising administering a
therapeutically-effective amount of one or more compounds of
Embodiment 25 or a salt, prodrug or antibody conjugate thereof.
[0127] Embodiment 29 relates to the method of Embodiment 28,
wherein the cancer is a solid-tumor cancer.
[0128] Embodiment 30 relates to the method of Embodiment 28,
wherein the cancer is selected from cervical, prostate, lung,
ovarian, breast, renal cell, and pancreatic cancers.
[0129] Embodiment 31 relates to the method of Embodiments 28-30,
wherein a therapeutically-effective amount of the one or more
compounds is administered at least twice within a 60 day
period.
[0130] Embodiment 32 relates to the method of Embodiments 28-31,
further comprising administering one or more of the compounds of
Embodiment 25 in combination with at least one other anticancer
agent.
* * * * *